rs1060501891

Positions:

• chr5-162068070-C-A
• chr5-162068070-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_198904.4(GABRG2):​c.71C>A​(p.Thr24Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T24A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GABRG2 NM_198904.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31

Genes affected

GABRG2 (HGNC:4087): (gamma-aminobutyric acid type A receptor subunit gamma2) This gene encodes a gamma-aminobutyric acid (GABA) receptor. GABA is the major inhibitory neurotransmitter in the mammlian brain, where it acts at GABA-A receptors, which are ligand-gated chloride channels. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. Mutations in this gene have been associated with epilepsy and febrile seizures. Multiple transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GABRG2
• BP4: Computational evidence support a benign effect (MetaRNN=0.20981118).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRG2	NM_198904.4	c.71C>A	p.Thr24Lys	missense_variant	1/10	ENST00000639213.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRG2	ENST00000639213.2	c.71C>A	p.Thr24Lys	missense_variant	1/10	1	NM_198904.4	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy, childhood absence 2;C1969810:Febrile seizures, familial, 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 03, 2016

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a GABRG2-related disease. This sequence change replaces threonine with lysine at codon 24 of the GABRG2 protein (p.Thr24Lys). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Benign	0.93
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.056
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.69	T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	-0.69	N;.;N;.;.;.;N;.;.
MutationTaster	Benign	0.72	D;D;D;D
PrimateAI	Benign	0.41	T
Polyphen		0.0	B;.;B;.;.;.;.;.;.
Vest4		0.42, 0.30
MutPred		0.64		Gain of ubiquitination at T24 (P = 0.0185);.;Gain of ubiquitination at T24 (P = 0.0185);.;Gain of ubiquitination at T24 (P = 0.0185);Gain of ubiquitination at T24 (P = 0.0185);Gain of ubiquitination at T24 (P = 0.0185);Gain of ubiquitination at T24 (P = 0.0185);Gain of ubiquitination at T24 (P = 0.0185);
MVP		0.52
MPC		0.088
ClinPred		0.67	D
GERP RS		4.1
Varity_R		0.071
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060501891; hg19: chr5-161495076;